YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases
Inna Rabinovich-Nikitin1 and Lorrie A. Kirshenbaum1,2
1The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology and
2Department of Pharmacology and Therapeutics Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Address correspondence to: Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Rm. 3016, 351 Taché Avenue, Winnipeg, Manitoba, Canada, R2H 2A6. Phone: 204.235.3661; Email: lkirshenbaum@sbrc.ca.
Find articles by Rabinovich-Nikitin, I. in: JCI | PubMed | Google Scholar
1The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology and
2Department of Pharmacology and Therapeutics Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Address correspondence to: Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Rm. 3016, 351 Taché Avenue, Winnipeg, Manitoba, Canada, R2H 2A6. Phone: 204.235.3661; Email: lkirshenbaum@sbrc.ca.
Find articles by Kirshenbaum, L. in: JCI | PubMed | Google Scholar
Published March 1, 2021 - More info
J Clin Invest. 2021;131(5):e146821. https://doi.org/10.1172/JCI146821.
© 2021 American Society for Clinical Investigation
Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.
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